DIPHENOXYLATE HYDROCHLORIDE W/ ATROPINE SULFATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DIPHENOXYLATE HYDROCHLORIDE W/ ATROPINE SULFATE (DIPHENOXYLATE HYDROCHLORIDE W/ ATROPINE SULFATE).
Diphenoxylate acts as an opioid agonist on mu-opioid receptors in the gastrointestinal tract, reducing peristalsis and increasing intestinal transit time. Atropine sulfate is added at subtherapeutic doses to deter abuse by causing unpleasant anticholinergic effects at high doses.
| Metabolism | Diphenoxylate is extensively metabolized in the liver to diphenoxylic acid (active metabolite) via ester hydrolysis; atropine is metabolized by hepatic CYP450 enzymes (primarily CYP3A4). |
| Excretion | Diphenoxylate is excreted primarily in feces (via biliary elimination) as the active metabolite difenoxin and its conjugates; approximately 14% is excreted renally as unchanged drug and metabolites. Atropine is excreted renally (30-50% unchanged) and partially in feces. |
| Half-life | Diphenoxylate: terminal half-life of 2.9-5.8 hours (active metabolite difenoxin: 12-14 hours). Atropine: terminal half-life of 2-4 hours. Clinical context: The long half-life of difenoxin contributes to sustained antidiarrheal effect. |
| Protein binding | Diphenoxylate: approximately 90% bound to plasma proteins. Atropine: 14-22% bound to albumin. |
| Volume of Distribution | Diphenoxylate: 24-31 L/kg (large Vd indicating extensive tissue distribution). Atropine: 1.7-2.9 L/kg. |
| Bioavailability | Oral: Diphenoxylate bioavailability is approximately 90% (as prodrug converted to active metabolite difenoxin); atropine bioavailability is 10-50% (extensive first-pass metabolism). |
| Onset of Action | Oral: 1-3 hours. |
| Duration of Action | 3-4 hours (antidiarrheal effect) per dose due to diphenoxylate; atropine's duration is 4-6 hours. Note: Extended use may lead to prolonged effect due to difenoxin accumulation. |
| Molecular Weight | 489.09 |
2.5-5 mg (diphenoxylate) orally 4 times daily until diarrhea controlled; maximum 20 mg/day (diphenoxylate).
| Dosage form | CAPSULE |
| Renal impairment | eGFR <30 mL/min: avoid use; eGFR 30-50 mL/min: use with caution, consider reduced dose or extended interval. |
| Liver impairment | Child-Pugh class B or C: avoid use due to risk of hepatic encephalopathy; Child-Pugh class A: use with caution. |
| Pediatric use | 0.3-0.4 mg/kg/day (diphenoxylate) in 4 divided doses; maximum 10 mg/day. Not recommended for children <2 years. |
| Geriatric use | Initiate at lower end of dosing range (2.5 mg orally 3-4 times daily); monitor for anticholinergic effects and constipation. |
| 1st trimester | Avoid due to anticholinergic effects and potential teratogenicity; atropine may cause fetal tachycardia. |
| 2nd trimester | Avoid; use only if clearly needed and no safer alternative exists. |
| 3rd trimester | Avoid near term; may cause CNS depression or anticholinergic effects in neonate. |
Clinical note
Comprehensive clinical and safety monograph for DIPHENOXYLATE HYDROCHLORIDE W/ ATROPINE SULFATE (DIPHENOXYLATE HYDROCHLORIDE W/ ATROPINE SULFATE).
| Placental transfer | Crosses placenta; both diphenoxylate and atropine are transferred to fetus. |
| Breastfeeding | Diphenoxylate is excreted into breast milk in small amounts; atropine may suppress lactation or cause anticholinergic effects in infant. Avoid breastfeeding due to potential serious adverse effects. |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to diphenoxylate or atropineObstructive jaundiceDiarrhea associated with pseudomembranous colitis or enterotoxin-producing bacteriaChildren under 6 years of age (due to atropine toxicity risk)
| Precautions | Risk of respiratory depression, especially in children, Potential for anticholinergic effects (e.g., urinary retention, blurred vision) due to atropine, Hepatic impairment may require dose adjustment, May cause dependence with prolonged use; abrupt discontinuation may precipitate withdrawal |
| Food/Dietary | Avoid alcohol consumption due to additive CNS depression. No specific food interactions, but maintain adequate fluid intake to prevent dehydration. Avoid high-fiber or high-fat meals that may worsen diarrhea. |
Loading safety data…
| Lactation Rating |
| L5 (Contraindicated) |
| Teratogenic Risk | Diphenoxylate/atropine is generally considered low-risk for major malformations. Animal studies have not shown teratogenicity at therapeutic doses. Human data are limited but reported doses fall below known atropine teratogenic thresholds. No increased risk of miscarriage or congenital anomalies has been conclusively documented. However, opioid use in late pregnancy may cause neonatal withdrawal syndrome, including irritability, hypertonia, and respiratory depression. Atropine may cause neonatal anticholinergic effects such as tachycardia and decreased gut motility if used near term. |
| Fetal Monitoring | Monitor maternal vital signs (heart rate, blood pressure) for anticholinergic effects. Assess bowel function; avoid prolonged use due to risk of toxic megacolon in inflammatory bowel disease. Observe neonate for signs of opioid withdrawal (e.g., poor feeding, jitteriness, respiratory depression) for 48-72 hours after delivery if used near term. Fetal heart rate monitoring may be considered if maternal opioid effects are significant. |
| Fertility Effects | No specific data on human fertility. Opioids may cause altered hypothalamic-pituitary-gonadal axis leading to decreased libido, anovulation, and menstrual irregularities in chronic users. Atropine has no known direct effect on fertility. Effects are reversible upon drug discontinuation. |
| Clinical Pearls | Diphenoxylate/atropine (Lomotil) acts on mu-opioid receptors in the gut to reduce peristalsis. Atropine is added in subtherapeutic doses to discourage abuse. Onset is 45-60 min, duration 3-4 h. Use only for acute diarrhea; avoid in infectious diarrhea (e.g., C. diff) due to risk of toxic megacolon. Can cause anticholinergic effects (dry mouth, blurred vision, urinary retention). Do not exceed recommended dose; high doses can produce opioid-like euphoria and respiratory depression. Contraindicated in children <6 years and patients with obstructive jaundice or paralytic ileus. |
| Patient Advice | Take exactly as prescribed; do not exceed recommended dose. · May cause drowsiness or dizziness; avoid driving or operating machinery until you know how it affects you. · Do not use for more than 2 days unless directed by your doctor. · Avoid alcohol and other CNS depressants (e.g., sedatives, tranquilizers). · Report severe abdominal pain, constipation, or bloody diarrhea immediately. · Keep out of reach of children; accidental overdose can cause severe respiratory depression. |